The Neurobiology and Neural Circuitry of Schizophrenia

Schizophrenia is a complex and heterogeneous neuropsychiatric disorder characterized by symptoms falling into three primary domains: positive symptoms (the presence of abnormal experiences or behaviors, such as delusions and hallucinations), negative symptoms (the diminution of normal functions, such as volition or emotional expression), and cognitive impairments such as difficulties with working memory and executive functioning.¹ In addition to these symptom domains, patients with schizophrenia have distinct alterations in brain circuitry and neurochemistry in different brain regions.² 

Gray Matter Volume Reductions and Neurodevelopmental Disruption 

Magnetic resonance imaging (MRI) studies have shown reductions in gray matter volume in individuals with schizophrenia compared to healthy controls. These deficits are particularly prominent in the prefrontal cortex, temporal lobes, anterior cingulate cortex, and hippocampal regions.² One recent analysis using cortical rendering of MRI data showed significantly reduced gray matter volume in patients with schizophrenia (P < 0.05, family-wise error corrected). Notably, some regions exhibited an accelerated rate of gray matter loss relative to controls.² 

Overactivity of the dopaminergic pathway in the associative striatum, a gray matter region involved in cognitive integration, contributes to the positive symptoms of schizophrenia.³ Simultaneously, underactivity in dopaminergic signaling within other gray matter regions in the frontal lobe and mesolimbic structures is thought to be associated with negative symptoms^.4 Additionally, reduced dopaminergic activity in the prefrontal cortex, a gray matter region critical for executive function, underlies cognitive impairment.⁵  

White Matter Deficits: Contributions to Negative Symptoms and Cognitive Impairment 

Insights from neuroimaging studies suggest involvement of white matter deficits in the functional deficits observed in patients with schizophrenia. In a 2015 study, frontotemporal tissue from individuals with schizophrenia showed reduced thickness and integrity compared with healthy controls, especially in the inferior longitudinal and arcuate fasciculi. These structural changes were most evident in patients with poorer functional status.⁶  

Specifically, imaging studies have found deficits in connectivity in patients with schizophrenia in three white matter tracts of interest: the corpus callosum, the cingulum bundle, and the arcuate fasciculus.7 These three white matter pathways are distinct in their anatomical positioning, neural connections, and functional roles.7 The cingulum bundle links various parts of the limbic cortex and is vital for processes such as memory integration.⁷ The corpus callosum facilitates communication between the brain’s hemispheres by connecting corresponding cortical regions, supporting auditory processing, motor coordination, and other cognitive functions.⁷ Meanwhile, the arcuate fasciculus bridges language and speech-related regions, extending from the caudal temporal and inferior parietal cortices to the frontal lobe, playing a key role in verbal communication.⁷ Additionally, the study found that antipsychotic treatment did not alter neurofilament levels of proteins that help maintain function in these regions, which was consistent with the observation that current antipsychotic medications primarily target positive symptoms of schizophrenia, with limited impact on cognitive impairment or negative symptoms.^1,7,8 

Treatment Implications 

Current antipsychotic medications primarily address the dopaminergic overactivity responsible for positive symptoms.³ However, they do not treat negative symptoms and cognitive impairment, which remains a major therapeutic challenge.^1,4,5 These domains are less responsive to existing treatments and predictive of long-term functional outcomes, such as social integration, employment, and independent living.⁹ 

Although antipsychotic medications have helped people with schizophrenia for nearly 70 years, all currently approved drugs work by blocking dopamine receptors.³ A deeper understanding of neural circuit dysfunction in schizophrenia may provide a foundation for developing targeted therapies. Antipsychotics and antidepressants with serotonergic mechanisms may improve negative symptoms.1  

Despite encouraging signs with existing therapies, additional research is urgently needed to develop more effective new treatments. To that end, researchers are working on new types of medications for schizophrenia that go beyond the usual dopaminergic therapies by targeting different systems in the brain. These include trace amine-associated receptors (TAAR), muscarinic receptors, and serotonin receptors.³ 

References: 

1.     Cerveri G, Gesi C, Mencacci C. Pharmacological treatment of negative symptoms in schizophrenia: update and proposal of a clinical algorithm. Neuropsychiatr Dis Treat. 2019;15:1525-1535. doi:10.2147/NDT.S201726.  
2.     Cropley VL, Klauser P, Lenroot RK, et al. Accelerated gray and white matter deterioration with age in schizophrenia. Am J Psychiatry. 2017;174:286-295. doi:10.1176/appi.ajp.2016.16050610 
3.     Correll CU, Abi-Dargham A, Howes O. Emerging treatments in schizophrenia. J Clin Psychiatry. 2022;83(1). doi:10.4088/JCP.SU21024IP1 
4.     Correll CU, Schooler NR. Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr Dis Treat. 2020;16:519-534. doi:10.2147/NDT.S225643 
5.     McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine, and the striatum: from biology to symptoms. Trends Neurosci. 2019;42:205-220. doi:10.1016/j.tins.2018.12.004  
6.     Behdinan T, Foussias G, Wheeler AL, et al. Neuroimaging predictors of functional outcomes in schizophrenia at baseline and 6-month follow-up. Schizophr Res. 2015;169(1-3):69-75. doi:10.1016/j.schres.2015.10.023 
7.     Schoonover KE, Farmer CB, Cash AE, Robets RC. Pathology of white matter integrity in three major white matter fasciculi: A post‐mortem study of schizophrenia and treatment status. Br J Pharmacol. 2019;176(8):1143-1155. doi:10.1111/bph.14612 
8.     Kesby JP, Eyles DW, McGrath JJ, Scott JG. Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience. Transl Psychiatry. 2018;8:30. doi:10.1038/s41398-017-0071-9 
9.     Mucci A, Galderisi S, Giberrtoni D, et al. Factors associated with real-life functioning in persons with schizophrenia in a 4-year follow-up study of the Italian network for research on psychoses. JAMA Psychiatry. 2021;78(5):550-559. doi:10.1001/jamapsychiatry.2020.4614 

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